tbuckley/cabot-search huggingface dataset:
Novel combination strategy of high intensity focused ultrasound (HIFU) and checkpoint blockade boosted by bioinspired and oxygen-supplied nanoprobe for multimodal imaging-guided cancer therapy
Authors: Rui Tang, Hongye He, Xiaohong Lin, Nianhong Wu, Li Wan, Qiaoqi Chen, Yaqin Hu, Chen Cheng, Yuting Cao, Xun Guo, Ying Zhou, Xialin Xiong, Min Zheng, Qi Wang, Faqi Li, Yang Zhou, Pan Li
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background High-intensity focused ultrasound (HIFU) has shown considerable promise in treating solid tumors, but its ultrasonic energy is easily attenuated, resulting in insufficient energy accumulation in the target area. Moreover, HIFU ablation alone may inevitably lead to the presence of residual tumors, which may cause tumor recurrence and metastasis. Here, we describe a synergistic regimen combining HIFU facilitation with immunomodulation based on a novel oxygen-carrying biomimetic perfluorocarbon nanoparticle (M@P-SOP) to stimulate immunogenic cell death in tumor cells while alleviating immune suppression tumor microenvironment. Methods M@P-SOP was prepared by double emulsion and film extrusion method. The anticancer and antimetastatic effects of M@P-SOP were evaluated on a preclinical transplanted 4T1 tumor model by combining HIFU and immunotherapy. Flow cytometry and immunofluorescence were used to clarify the potential mechanism of HIFU+M@P-SOP and their role in anti-programmed death ligand-1 (PD-L1) therapy. Results Guided by photoacoustic/MR/ultrasound (US) multimodal imaging, M@P-SOP was abundantly enriched in tumor, which greatly enhanced HIFU’s killing of tumor tissue in situ, induced stronger tumor immunogenic cell death, stimulated dendritic cell maturation and activated CD8 + T cells. At the same time, M@P-SOP released oxygen to alleviate the tumor hypoxic environment, repolarizing the protumor M2-type macrophages into antitumor M1-type. With concurrent anti-PD-L1 treatment, the antitumor immune response was further amplified to the whole body, and the growth of mimic distant tumor was effectively suppressed. Conclusions Our findings offer a highly promising HIFU synergist for effectively ameliorating acoustic and hypoxia environment, eventually inhibiting tumor growth and metastasis by stimulating host’s antitumor immunity under HIFU ablation, especially in synergizing with PD-L1 antibody immunotherapy.
Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models
Authors: Vikash Kansal, Andre J Burnham, Brendan L C Kinney, Nabil F Saba, Chrystal Paulos, Gregory B Lesinski, Zachary S Buchwald, Nicole C Schmitt
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Anti-PD-1 immune checkpoint blockade is approved for first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but few patients respond. Statin drugs (HMG-CoA reductase inhibitors) are associated with superior survival in several cancer types, including HNSCC. Emerging data suggest that manipulation of cholesterol may enhance some aspects of antitumor immunity. Methods We used syngeneic murine models (mouse oral cancer, MOC1 and TC-1) to investigate our hypothesis that a subset of statin drugs would enhance antitumor immunity and delay tumor growth. Results Using an ex vivo coculture assay of murine cancer cells and tumor infiltrating lymphocytes, we discovered that all seven statin drugs inhibited tumor cell proliferation. Simvastatin and lovastatin also enhanced T-cell killing of tumor cells. In mice, daily oral simvastatin or lovastatin enhanced tumor control and extended survival when combined with PD-1 blockade, with rejection of MOC1 tumors in 30% of mice treated with lovastatin plus anti-PD-1. Results from flow cytometry of tumors and tumor-draining lymph nodes suggested T cell activation and shifts from M2 to M1 macrophage predominance as potential mechanisms of combination therapy. Conclusions These results suggest that statins deserve further study as well-tolerated, inexpensive drugs that may enhance responses to PD-1 checkpoint blockade and other immunotherapies for HNSCC.
Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis
Authors: Richard S P Huang, David P Carbone, Gerald Li, Alexa Schrock, Ryon P Graf, Liangliang Zhang, Karthikeyan Murugesan, Jeffrey S Ross, Khaled Tolba, Jacob Sands, Geoffrey R Oxnard, David Spigel
Journal: Journal for ImmunoTherapy of Cancer (2023)

For patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform the optimal choice for individual patients. Here, we examined the complementary roles of tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) to inform first-line therapy using a large real-world (rw) data set.
London International Consensus and Delphi study on hamstring injuries part 1: classification
Authors: Bruce M Paton, Nick Court, Michael Giakoumis, Paul Head, Babar Kayani, Sam Kelly, Gino M M J Kerkhoffs, James Moore, Peter Moriarty, Simon Murphy, Ricci Plastow, Noel Pollock, Paul Read, Ben Stirling, Laura Tulloch, Nicol van Dyk, Mathew G Wilson, David Wood, Fares Haddad
Journal: British Journal of Sports Medicine (2023)

Muscle injury classification systems for hamstring injuries have evolved to use anatomy and imaging information to aid management and prognosis. However, classification systems lack reliability and validity data and are not specific to individual hamstring muscles, potentially missing parameters vital for sport-specific and activity-specific decision making. A narrative evidence review was conducted followed by a modified Delphi study to build an international consensus on best-practice decision-making for the classification of hamstring injuries. This comprised a digital information gathering survey to a cohort of 46 international hamstring experts (sports medicine physicians, physiotherapists, surgeons, trainers and sports scientists) who were also invited to a face-to-face consensus group meeting in London . Fifteen of these expert clinicians attended to synthesise and refine statements around the management of hamstring injury. A second digital survey was sent to a wider group of 112 international experts. Acceptance was set at 70% agreement. Rounds 1 and 2 survey response rates were 35/46 (76%) and 99/112 (88.4%) of experts responding. Most commonly, experts used the British Athletics Muscle Injury Classification (BAMIC) (58%), Munich (12%) and Barcelona (6%) classification systems for hamstring injury. Issues identified to advance imaging classifications systems include: detailing individual hamstring muscles, establishing optimal use of imaging in diagnosis and classification, and testing the validity and reliability of classification systems. The most used hamstring injury classification system is the BAMIC. This consensus panel recommends hamstring injury classification systems evolve to integrate imaging and clinical parameters around: individual muscles, injury mechanism, sporting demand, functional criteria and patient-reported outcome measures. More research is needed on surgical referral and effectiveness criteria, and validity and reliability of classification systems to guide management.
London International Consensus and Delphi study on hamstring injuries part 2: operative management
Authors: Ricci Plastow, Gino M M J Kerkhoffs, David Wood, Bruce M Paton, Babar Kayani, Noel Pollock, Nick Court, Michael Giakoumis, Paul Head, Sam Kelly, James Moore, Peter Moriarty, Simon Murphy, Paul Read, Ben Stirling, Laura Tulloch, Nicol van Dyk, Mathew Wilson, Fares Haddad
Journal: British Journal of Sports Medicine (2023)

The key indications for surgical repair of hamstring injuries (HSIs) remain unclear in the literature due to a lack of high-level evidence and expert knowledge. The 2020 London International Hamstring Consensus meeting aimed to highlight clear surgical indications and to create a foundation for future research. A literature review was conducted followed by a modified Delphi process, with an international expert panel. Purposive sampling was used with two rounds of online questionnaires and an intermediate round involving a consensus meeting. The initial information gathering (round 1) questionnaire was sent to 46 international experts, which comprised open-ended questions covering decision-making domains in HSI. Thematic analysis of responses outlined key domains, which were evaluated by a smaller international subgroup (n=15) comprising clinical academic sports medicine physicians, physiotherapists and orthopaedic surgeons in a consensus meeting. After group discussion of each domain, a series of consensus statements were prepared, debated and refined. A round 2 questionnaire was sent to 112 international hamstring experts to vote on these statements and determine level of agreement. The consensus threshold was set a priori at 70% agreement. Rounds 1 and 2 survey respondents were 35/46 (76%) and 99/112 (88.4%), respectively. The consensus group agreed that the indications for operative intervention included: gapping at the zone of tendinous injury (87.2% agreement) and loss of tension (70.7%); symptomatic displaced bony avulsions (72.8%); and proximal free tendon injuries with functional compromise refractory to non-operative treatment (72.2%). Other important considerations for operative intervention included: the demands of the athlete/patient and the expected functional outcome (87.1%) based on the anatomy of the injury; the risk of functional loss/performance deficit with non-operative management (72.2%); and the capacity to restore anatomy and function (87.1%). Further research is needed to determine whether surgery can reduce the risk of reinjury as consensus was not reached within the whole group (48.2%) but was agreed by surgeons (70%) in the cohort. The consensus group did not support the use of corticosteroids or endoscopic surgery without further evidence. These guidelines will help standardise treatment of HSIs, specifically the indications and decision-making for surgical intervention.
The association between hepatic steatosis and incident cardiovascular disease, cancer, and all-cause mortality in a US multicohort study
Authors: Heidi S. Ahmed, Na Wang, J. Jeffrey Carr, Jingzhong Ding, James G. Terry, Lisa B. VanWagner, Lifang Hou, Yuankai Huo, Joseph Palmisano, Yinan Zheng, Emelia J. Benjamin, Michelle T. Long
Journal: Hepatology (2023)

NAFLD strongly associates with cardiovascular disease (CVD) risk factors; however, the association between NAFLD and incident CVD, CVD-related mortality, incident cancer, and all-cause mortality is unclear.
Regulatory role and translational potential of CCL11 in liver fibrosis
Authors: Ming Kong, Wenhui Dong, Aoqi Kang, Yameng Kuai, Tongchang Xu, Zhiwen Fan, Longqing Shi, Donglin Sun, Yunjie Lu, Zilong Li, Yong Xu
Journal: Hepatology (2023)

Myofibroblasts are considered the major effector cell type of liver fibrosis and primarily derived from hepatic stellate cells (HSCs). In the present study, we investigated the contribution of C-C motif chemokine (CCL11) to HSC-myofibroblast trans -differentiation and its implication in liver fibrosis.We report that CCL11 levels were elevated in HSCs, but not in hepatocytes or Kupffer cells, isolated from mice with liver fibrosis compared with the control mice. CCL11 levels were also up-regulated by 2 pro-fibrogenic growth factors TGF-β and platelet derived growth factor in cultured HSCs. Mechanistically, zinc finger factor 281 bound to the CCL11 promoter and mediated CCL11 trans -activation in HSCs. Depletion of CCL11 attenuated whereas treatment with recombinant CCL11 promoted HSC activation. Further, global CCL11 deletion ( CCL11-/- ) or HSC/myofibroblast-specific CCL11 knockdown mitigated fibrogenesis in mice. RNA-sequencing revealed that CCL11 might regulate HSC activation by stimulating the transcription of Jagged 1. Reconstitution of Jagged 1 restored the fibrogenic response in CCL11-/- mice. Finally, several targeting strategies that aimed at blockading CCL11 signaling, either by administration of an antagonist to its receptor C-C motif chemokine receptor 3 or neutralizing antibodies against CCL11/C-C motif chemokine receptor 3, ameliorated liver fibrosis in mice.Our data unveil a previously unrecognized role for CCL11 in liver fibrosis and provide proof-of-concept evidence that targeting CCL11 can be considered as an effective therapeutic approach.
Real-world COVID-19 vaccine effectiveness against the Omicron BA.2 variant in a SARS-CoV-2 infection-naive population
Authors: Jonathan J. Lau, Samuel M. S. Cheng, Kathy Leung, Cheuk Kwong Lee, Asmaa Hachim, Leo C. H. Tsang, Kenny W. H. Yam, Sara Chaothai, Kelvin K. H. Kwan, Zacary Y. H. Chai, Tiffany H. K. Lo, Masashi Mori, Chao Wu, Sophie A. Valkenburg, Gaya K. Amarasinghe, Eric H. Y. Lau, David S. C. Hui, Gabriel M. Leung, Malik Peiris, Joseph T. Wu
Journal: Nature Medicine (2023)

The SARS-CoV-2 Omicron variant has demonstrated enhanced transmissibility and escape of vaccine-derived immunity. Although first-generation vaccines remain effective against severe disease and death, robust evidence on vaccine effectiveness (VE) against all Omicron infections, irrespective of symptoms, remains sparse. We used a community-wide serosurvey with 5,310 subjects to estimate how vaccination histories modulated risk of infection in infection-naive Hong Kong during a large wave of Omicron BA.2 epidemic in January-July 2022. We estimated that Omicron infected 45% (41-48%) of the local population. Three and four doses of BNT162b2 or CoronaVac were effective against Omicron infection 7 days after vaccination (VE of 48% (95% credible interval 34-64%) and 69% (46-98%) for three and four doses of BNT162b2, respectively; VE of 30% (1-66%) and 56% (6-97%) for three and four doses of CoronaVac, respectively). At 100 days after immunization, VE waned to 26% (7-41%) and 35% (10-71%) for three and four doses of BNT162b2, and to 6% (0-29%) and 11% (0-54%) for three and four doses of CoronaVac. The rapid waning of VE against infection conferred by first-generation vaccines and an increasingly complex viral evolutionary landscape highlight the necessity for rapidly deploying updated vaccines followed by vigilant monitoring of VE.
Polygenic Risk and Episode Polarity Among Individuals With Bipolar Disorder
Authors: Sofie Hasseris, Clara Albiñana, Bjarni J. Vilhjalmsson, Preben B. Mortensen, Søren D. Østergaard, Katherine L. Musliner
Journal: American Journal of Psychiatry (2023)

Objective: The authors investigated associations between polygenic liabilities for bipolar disorder, major depression, and schizophrenia and episode polarity among individuals with bipolar disorder. Methods: The sample consisted of 2,705 individuals diagnosed with bipolar disorder at Danish psychiatric hospitals between January 1995 and March 2017. DNA was obtained from dried blood spots collected at birth as part of routine screening. Polygenic risk scores (PRSs) for bipolar disorder, major depression, and schizophrenia were generated using a meta-PRS method combining internally and externally trained components. Associations between PRS and polarity at first episode, polarity at any episode, and number of episodes with a given polarity were evaluated for each disorder-specific PRS using logistic and negative binominal regressions adjusted for the other two PRSs, age, sex, genotype platform, and five ancestral principal components. Results: PRS for bipolar disorder was positively associated with any manic episodes (odds ratio=1.23, 95% CI=1.09–1.38). PRS for depression was positively associated with any depressive (odds ratio=1.11, 95% CI=1.01–1.23) and mixed (odds ratio=1.15, 95% CI=1.03–1.28) episodes and negatively associated with any manic episodes (odds ratio=0.76, 95% CI=0.69–0.84). PRS for schizophrenia was positively associated with any manic episodes (odds ratio=1.13, 95% CI=1.01–1.27), but only when psychotic symptoms were present (odds ratio for psychotic mania: 1.27, 95% CI=1.05–1.54; odds ratio for nonpsychotic mania: 1.06, 95% CI=0.93–1.20). These patterns were similar for first-episode polarity and for the number of episodes within each pole. Conclusions: PRSs for bipolar disorder, major depression, and schizophrenia are associated with episode polarity and psychotic symptoms in a congruent manner among individuals with bipolar disorder.
Moderate Alcohol Consumption and Depression: A Marginal Structural Model Approach Promoting Causal Inference
Authors: Rachel Visontay, Louise Mewton, Tim Slade, Izzuddin M. Aris, Matthew Sunderland
Journal: American Journal of Psychiatry (2023)

Moderate alcohol consumption is associated with decreased risk for depression, but it remains unclear whether this is a causal relationship or a methodological artifact. To compare the effects of consistent abstinence and occasional, moderate, and above-guideline alcohol consumption throughout early to middle adulthood on depression at age 50, the authors conducted a secondary analysis of the National Longitudinal Survey of Youth 1979 cohort and employed a marginal structural model (MSM) approach.Baseline was set at 1994, when individuals were ages 29-37. The MSM incorporated measurements of alcohol consumption in 1994, 2002, and 2006, baseline and time-varying covariates, and repeated measurements with the Center for Epidemiologic Studies Depression Scale-Short Form (CES-D-SF). A total of 5,667 eligible participants provided valid data at baseline, 3,593 of whom provided valid outcome data. The authors used all observed data to predict CES-D-SF means and rates of probable depression for hypothetical trajectories of consistent alcohol consumption.The results approximated J-curve relationships. Specifically, both consistent occasional and consistent moderate drinkers were predicted to have reduced CES-D-SF scores and rates of probable depression at age 50 compared with consistent abstainers (CES-D-SF scores: b=-0.84, 95% CI=-1.47, -0.11; probable depression: odds ratio=0.58, 95% CI=0.36, 0.88 for consistent occasional drinkers vs. abstainers; CES-D-SF scores: b=-1.08, 95% CI=-1.88, -0.20; probable depression: odds ratio=0.59, 95% CI=0.26, 1.13 for consistent moderate drinkers vs. consistent abstainers). Consistent above-guideline drinkers were predicted to have slightly increased risk compared with consistent abstainers, but this was not significant. In sex-stratified analyses, results were similar for females and males.This study contributes preliminary evidence that associations between moderate alcohol consumption and reduced risk for depression may reflect genuine causal effects. Further research using diverse methodologies that promote causal inference is required.
Shared and Unique Changes in Brain Connectivity Among Depressed Patients After Remission With Pharmacotherapy Versus Psychotherapy
Authors: Boadie W. Dunlop, Jungho Cha, Ki Sueng Choi, Justin K. Rajendra, Charles B. Nemeroff, W. Edward Craighead, Helen S. Mayberg
Journal: American Journal of Psychiatry (2023)

Objective: The authors sought to determine the shared and unique changes in brain resting-state functional connectivity (rsFC) between patients with major depressive disorder who achieved remission with cognitive-behavioral therapy (CBT) or with antidepressant medication. Methods: The Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) trial randomized adults with treatment-naive major depressive disorder to 12 weeks of treatment with CBT (16 1-hour sessions) or medication (duloxetine 30–60 mg/day or escitalopram 10–20 mg/day). Resting-state functional MRI scans were performed at baseline and at week 12. The primary outcome was change in the whole-brain rsFC of four seeded brain networks among participants who achieved remission. Results: Of the 131 completers with usable MRI data (74 female; mean age, 39.8 years), remission was achieved by 19 of 40 CBT-treated and 45 of 91 medication-treated patients. Three patterns of connectivity changes were observed. First, those who remitted with either treatment shared a pattern of reduction in rsFC between the subcallosal cingulate cortex and the motor cortex. Second, reciprocal rsFC changes were observed across multiple networks, primarily increases in CBT remitters and decreases in medication remitters. And third, in CBT remitters only, rsFC increased within the executive control network and between the executive control network and parietal attention regions. Conclusions: Remission from major depression via treatment with CBT or medication is associated with changes in rsFC that are mostly specific to the treatment modality, providing biological support for the clinical practice of switching between or combining these treatment approaches. Medication is associated with broadly inhibitory effects. In CBT remitters, the increase in rsFC strength between networks involved in cognitive control and attention provides biological support for the theorized mechanism of CBT. Reducing affective network connectivity with motor systems is a shared process important for remission with both CBT and medication.
Microphysiological Drug‐Testing Platform for Identifying Responses to Prodrug Treatment in Primary Leukemia
Authors: Furkan Gökçe, Alicia Kaestli, Christian Lohasz, Martina de Geus, Hans‐Michael Kaltenbach, Kasper Renggli, Beat Bornhauser, Andreas Hierlemann, Mario Modena
Journal: Advanced Healthcare Materials (2023)

Despite increasing survival rates of pediatric leukemia patients over the past decades, the outcome of some leukemia subtypes has remained dismal. Drug sensitivity and resistance testing on patient-derived leukemia samples provide important information to tailor treatments for high-risk patients. However, currently used well-based drug screening platforms have limitations in predicting the effects of prodrugs, a class of therapeutics that require metabolic activation to become effective. To address this issue, a microphysiological drug-testing platform is developed that enables co-culturing of patient-derived leukemia cells, human bone marrow mesenchymal stromal cells, and human liver microtissues within the same microfluidic platform. This platform also enables to control the physical interaction between the diverse cell types. Herein, it is made possible to recapitulate hepatic prodrug activation of ifosfamide in their platform, which is very difficult in traditional well-based assays. By testing the susceptibility of primary patient-derived leukemia samples to the prodrug ifosfamide, sample-specific sensitivities to ifosfamide in primary leukemia samples are identified. The microfluidic platform is found to enable the recapitulation of physiologically relevant conditions and the testing of prodrugs including short-lived and unstable metabolites. The platform holds great potential for clinical translation and precision chemotherapy selection.